诊断

Review

Genetic Association on Radiation Induced Mucosal and Skin Toxicity in Patients with Nasopharyngeal Carcinoma

Isabella Wai Yin Cheuk, Vincent Wing Cheung Wu

 

Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hunghom, Hong Kong

Corresponding Author: Vincent WC Wu, PhD, Email: htvinwu@polyu.edu.hk

 

 

Citation: Cheuk IWY, Wu VWC. Genetic association on radiation induced mucosal and skin toxicity in patients with nasopharyngeal carcinoma. J Nasopharyng Carcinoma, 2014, 1(7): e7. doi:10.15383/jnpc.7.

Funding: This work was supported by grant from the Hong Kong Polytechnic University (RPFG).

Competing interests: The authors have declared that no competing interests exist.

Conflict of interest: None.

Copyright: http://journalofnasopharyngealcarcinoma.org/Resource/image/20140307/20140307234733_0340.png2014 By the Editorial Department of Journal of Nasopharyngeal Carcinoma. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

 

 

Abstract: Radiation therapy (RT) is the primary treatment for many head and neck cancers including nasopharyngeal carcinoma (NPC). While prognosis has been greatly improved with the advancement of RT technique, radiation-induced complications especially normal tissue surrounding tumour volume is unavoidable. Genetic factors are thought to be the most important factors contributing to individual variation in radiation sensitivity. Over 120 studies have been published since year 2000 to investigate the association of genetic variants to radiation-induced toxicities in various types of cancer. Candidate gene approach is the most commonly used approach in published studies, including studies in patients with NPC. Skin and mucosal toxicities are two of the most common radiation induced complications in the radiotherapy of NPC patients. However, studies focused on radiation toxicity in NPC patients are limited. Published literatures focused on genetic variations and radiation sensitivity in NPC patients are summarized in this review, and recommendations for future studies are also suggested.

Keywords: Nasopharyngeal carcinoma; Radiation; Genetic association; Skin toxicity

 

 

1.     Introduction

Nasopharyngeal carcinoma (NPC), an endemic disease in Southern China including Hong Kong, is primarily treated by radiotherapy (RT) due to its deep-seated anatomical location and its relatively high sensitivity to radiation, particularly for thehighest incidence subtype, undifferentiated carcinoma [1]. RT has evolved from two-dimensional conventional RT techniques to three-dimensional intensity-modulated radiation therapy (IMRT) techniques to increase dose conformity to target volume [2]. Overall survival rate and local regional control rate for NPC, especially for advanced T3-4 diseases, have been improved from 50-75% to about 90% with advanced RT technique [3]. Chemotherapy is used concurrently with RT to increase local regional control rate for advance stage disease and to reduce rate of distant metastasis, although the use of adjuvant chemotherapy is still under debate [3]. Since the median age of NPC patients is around 50s, quality of life in these patients is one of the major concerns in providing better patient care. Acute and late effects of radiation induced toxicities have been receiving growing interest in the field of radiation oncology, since radiation induced toxicities are unavoidable and it is difficult to identify which patients are with higher risk of developing severe radiation induced toxicities before the start of RT. Acute reactions such as dermatitis, dysphagia, and mucositis and late complications such as xerostomia and neck fibrosis are some of the most common radiation induced toxicities regardless of any RT techniques in NPC patients. Dose escalation to target volume can be achieved by IMRT without compromising critical organs at risk (OAR) [4]. While incidence of radiation induced toxicities such as xerostomia, temporal lobe neuropathy and cranial nerve palsy have been greatly reduced thanks to the improvement of dose-sparing technique achieved by IMRT [5,6], skin and mucosal toxicities are unavoidable and remain the major treatment-related complications that may interrupt treatment schedule. Around 48% and 16% of NPC patients treated by RT alone suffered from grade 3 or above mucositis and skin reactions respectively [7]. With the use of chemotherapeutic agents such as cisplatin, the incidence of ototoxicity is significantly higher in patients treated with concurrent chemotherapy and RT (CRT) [8]. Over 61% of NPC patients treated with CRT suffered from grade 3 or above acute mucositis [8]. The overall incidence of acute toxicity in any aspect was 83.2% and 53% for patients treated with CRT and RT respectively [8]. In terms of late toxicity, about 5% of NPC patients suffered from neck fibrosis treated with RT alone or CRT [8]. Treatment of radiation induced toxicities is mainly palliative since there is no effective way to prevent the occurrence of radiation induced toxicities. Palifermin, a recombinant truncated human keratinocyte growth factor (KGF) protein, has been showed to reduce the incidence of severe oral mucositis in two clinical trials with head and neck cancer patients. Management of acute skin reactions include symptom-relieving agents such as moisturizing cream and hydrocortisone creams while anti-inflammatory and antioxidant treatments are used for late fibrosis [9,10].

 

2.     Risk Factors Contributing To Variations In Normal Tissue Radiation Sensitivity

Patients receiving similar treatment modality have been found to experience different levels of radiation induced toxicities. There are probably several risk factors contributing to the individual variations in normal tissue sensitivity to radiation. One of the risk factors in increasing the risk of radiation induced complications is treatment-related. The correlation between total irradiated volume and complication risk has been reported in many cancers [11]. For breast cancer patients with larger breast volume, higher risk of suffering severe skin reactions has been found. Correlation of irradiated volume in lung cancer and liver cancer patients and increased risk of radiation induced toxicities have also been reported [11]. Use of RT techniques and chemotherapeutic agents, in addition to total radiation dose and number of fractions, may contribute to the increase of developing radiation induced complications [9,11]. Patient’s clinical characteristic is another important confounding factor that increased risk of developing radiation induced complications. Age, gender, medical complications and lifestyles such as smoking and drinking habits are patient-related risk factors [11]. However, up to 80% of the radiation induced toxicities cannot be explained by these known factors [12]. Genetic factors seem to be a most important underlying factors contributing to variation in radiosensitivity in normal tissue. Several genes have been identified throughout the past years that are related to increase radiosensitivity. Patients with genetic disorders such as Ataxia-telangiectasia and Fanconi’s anemia are known to be hypersensitivity to radiation due to truncated mutations in genes responsible for cell cycle regulation and DNA repair pathways, such as ataxia-telangiectasia mutated (ATM), DNA ligase IV (LIG4), and genes belong to Fanconi anaemia complementation group (FANC) family [12-15]. RT induces cell death mainly through the generation of reactive free radicals that interact with DNA, RNA, proteins, and plasma membrane [16]. Many signal transduction pathways are activated by DNA double-strand break (DSB) to repair DNA damages, since DSB is the primary lethal cell damage during RT [17]. ATM protein recognizes the complexes formed by DSBs and DNA repair proteins and the activity of ATM further activates other proteins such as transcription factors p53 [17]. Genes that involved in cell cycle checkpoint, DNA repair, and removal of reactive free radicals, such as nuclear factor kappa-B (NF-κB), superoxide dismutase (SOD), transforming growth factor beta (TGFβ), p53, tumour necrosis factor (TNF-α), and x-ray repair cross-complementing protein 1 (XRCC1) are activated by the DNA damages [16,18]. As a result, many genes that are associated with cell cycle regulation and DNA repair and their association to radiation induced complications have been investigated using candidate gene approach. Candidate gene approach and genome-wide association study (GWAS) are the two approaches used in genetic association studies. Candidate gene approach is a hypothesis-driven approach that is useful in studying single nucleotide polymorphisms (SNPs) and other types of genetic variants in genes with known biological roles in disease or phenotype of interest [19]. In contrast, GWAS is a hypothesis-free approach that prior knowledge of functional roles of SNPs in phenotype of interest is not required [20]. A dense set of SNPs is captured by GWAS comprehensively and unbiasedly. Several susceptibility loci in complex diseases such as diabetes have been identified in GWAS [20].

 

3.     Genetic Association Studies of Radiation Induced Toxicities in NPC

A literature search was performed on PubMed using a combination of keywords “radiotherapy or radiation therapy”, “radiation induced or radiosensitivit or hypersensitivit or radiotoxicit or normal tissue toxicity or complication”, and “polymorphism or single nucleotide polymorphism or SNP or genetic variant” (as of December 14, 2013). Over 120 published original and review articles were identified through literature search, manual search of citations from identified articles and selected journals (Figure 1). Candidate gene approach is the most commonly used in identified articles. Among these articles, only 4 articles included NPC patients, and 3 out of 4 articles were published by the same research group [21-24]. A summary characteristic of studies included NPC patients and data from our group (unpublished data) is shown is Table 1. Positive findings from included studies are summarized in Table 2. With the low incidence of NPC worldwide except endemic areas [1], it is not surprising that there is a lack of information on genetic association study on radiation induced toxicities in NPC patients Even with the inclusion of studies focused on radiation induced toxicities in head and neck cancers [25-28], the total number of studies is still limited (data not shown). All five studies are retrospective, case-control studies with different classification of “normal” and “severe” toxicity. Among genetic association studies included NPC patients, skin reactions and mucositis are the major toxicities of interest. While genetic association to acute skin reactions and acute mucositis was evaluated in two studies, the other three studies published by the same research group focused on subcutaneous and deep tissue fibrosis only. The largest sample size among the five studies is 155 with median 40 months of follow-up period after RT [21]. Genes investigated in these studies are involved in cell cycle regulations (ATM, CDKN1A, HDM2, TP53), inflammatory response (TGFβ1), DNA repair (LIG4, XRCC1, XRCC3, XRCC4, XRCC5), and endogenous oxidative stress defense (SOD2). It is interesting to note that genetic variant rs25487 (Arg399Gln) located in XRCC1 was associated with increased risk of acute dermatitis and acute mucositis in study by Li et al. while in study by Alsbeih et al., the minor allele was associated with lower risk of developing subcutaneous and deep skin fibrosis (Odd ratio = 0.41, CI = 0.21-0.79) [21,22]. Study by Pratesi et al. included seven types of head and neck cancers also showed increased risk of rs25487 to acute mucositis (OR = 3.01, CI = 1.27-7.11) [27]. However, these significant associations were unable to be replicated by our group with similar sample size (unpublished data). Conflicting results may be due to variation in control and case classification, treatment modality, population stratification for studies with Chinese NPC patients, allele frequency in different ethnic groups, and other confounding factors such as patient-related clinical information. Effect size of common genetic variants may be small to moderate that a larger sample size is needed to validate these positive findings.

 

 

Figure1

Figure 1. Number of genetic association studies from 2001-2013 (as of December 14, 2013).

 

 

 

Table 1. Summary characteristics of genetic association studies included NPC patients only

First author

Year of Publication

Origin

Study Design

Sample size

Mean/Median age

Gene

Treatment method

Genotyping method

Grading system

Control and case classification

Endpoint

Li [22]

2013

China

Retrospective, case-control

114

49.6 (19-76)

XRCC1

RT/CRT

RFLP

CTCAE v3.0

Control: Grade 1-2

 

Case: Grade 3

Acute dermatitis, acute mucositis

Alsbeih [21]

2013

Saudi Arabic

Retrospective, case-control

155

47 (15-77)

ATM

XRCC1

XRCC3

XRCC4

XRCC5

PRKDC

LIG4

TP53

HDM2

CDKN1A

TGFB1

3DCRT

Direct sequencing

RTOG

Control: Grade 0-2

 

Case: Grade 3-4

Subcutaneous and deep tissue fibrosis

Alsbeih [23]

2010

Saudi Arabic

Retrospective, case-control

60

50 (18-77)

TGFβ1

XRCC1

3DCRT

Direct sequencing

RTOG

Control: Grade 0-1

 

Case: Grade 2-3

Subcutaneous and deep tissue fibrosis

Alsbeih [24]

2008

Saudi Arabic

Retrospective, case-control

50

49 (18-71)

XRCC1

XRCC3

3DCRT

Direct sequencing

RTOG

Control: Grade 0-1

 

Case: Grade 2-3

Subcutaneous and deep tissue fibrosis

Cheuk

unpublished data

Hong Kong

Retrospective, case-control

120

54 (20-75)

ATM

SOD2

TGFβ1

TP53

XRCC1

XRCC3

RT/CRT

RFLP and UPr

RTOG

Control: Grade 0-1

 

Case: Grade 2-3

Acute skin reactions, acute mucotisits, and chronic neck fibrosis

Abbreviation: RT = Radiotherapy; 3DCRT = Three-dimensional conformal radiotherapy; CRT = Concurrent chemotherapy and radiotherapy; RFLP = Restriction fragment length polymorphism; UPr = Unlabeled Probe Melting Analysis; CTCAE = Common Terminology Criteria for Adverse Events; RTOG = Radiation Therapy Oncology Group.

 

 

 

 

 

Table 2. Positive findings from genetic association studies included NPC patients only

First author

Year of Publication

Endpoint

Polymorphism (s)

Mode of inheritance

OR (95% CI)

Li [22]

2013

Acute dermatitis

 

Acute mucositis

XRCC1 G/A (rs25487)

Genotype

2.65 (1.04-6.73)

 

2.11 (0.95-4.66)

Alsbeih [21]

2013

Subcutaneous and deep tissue fibrosis

 

ATM G/A (rs1801516)

 

HDM2 T/G (rs2279744)

 

HDM2 T/A (rs1196333)

 

TGFβ1 C/T (rs1800469)

 

XRCC1 G/A (rs25487)

 

XRCC5 T/C (rs10510677)

 

Allele

2.86 (1.18-6.48)

 

0.49 (0.29-0.84)

 

0.13 (0.02-0.99)

 

0.57 (0.34-0.96)

 

0.41(0.21-0.79)

 

0.39 (0.17-0.91)

Alsbeih [23]

2010

Subcutaneous and deep tissue fibrosis

 

TGFβ1 C/T (rs1800470)

 

XRCC1 G/A (rs25487)

 

Allele*

0.41 (0.20-0.86)

 

0.30 (0.10-0.89)

Alsbeih [24]

2008

Subcutaneous and deep tissue fibrosis

XRCC1 G/A (rs25487)

Allele*

0.31 (0.09-1.04)

Abbreviation: OR = odd ratio; CI = confidence interval.

*ORs of both genotype and allele were calculated; only the most significant results were shown.

 

 

 

 

4.     Reports In Other Cancers

While there is still lack of available information for NPC-related radiation induced toxicities, studies of genetic association in other cancers have changed from candidate gene approach to GWAS to identify genetic variants that are associated with ethnic group and disease-specific radiation induced toxicities. In addition, several meta-analysis have been published and addressed on common radiation induced toxicities arose in different cancers. A validation study included 1613 breast cancer and prostate cancer patients showed no association between radiation toxicity and 92 SNPs in 46 genes [29]. A replication study using breast cancer patients from three independent European cohorts showed that a SNP located in TNF-α may be associated to radiation toxicity [30]. Association of genetic variants located in heat shock protein beta-1 (HSPβ1) to risk of radiation induced pneumonitis was validated in two independent cohorts of non-small cell lung cancer patients [31]. The first GWAS focusing on radiation induced toxicities in African prostate cancer identified a genetic variant located in follicle-stimulating hormone receptor (FSHR) that involved in testis development and function is associated with erectile dysfunction [32]. A two-stage GWAS performed by the same research group included mainly European ancestry showed that this SNP may not be the universal biomarker for all ethnic groups but an ethnic group and prostate cancer specific biomarker [33]. Two research groups published meta-analysis of genetic variantrs1800469 in TGFβ1 and association to fibrosis in breast cancer patients and mixed cancer patients [34,35]. Results from these studies suggested that individual SNP may be ethnic-group and complication-specific that may not be used as universal biomarker to predict all types of toxicities induced in different types of cancers.

Conclusions And Future Directions

While significant results were reported in many genetic association studies using candidate gene approach, these results were unable to replicate in subsequent studies with larger sample size. In addition, results were often conflicting. Future studies should include large number of samples, prospectively and retrospectively, in order to perform well-designed study with adequate statistical power. Two ways to overcome sample size limitation are to perform meta-analysis and to collaborate with other research groups. One limitation of meta-analysis is that adequate information may not be able to obtain through literature search since positive findings are more likely to be published than negative findings. In order to enhance data pooling for genetic association studies, a 18-item checklist guideline Strengthening the Reporting Of Genetic Association studies in Radiogenomics (STROGAR) was suggested by the Radiogenomic consortium [36,37]. This guideline was modified based on the STrengthening the REporting of Genetic Association Studies (STREGA) recommendation [38] to include information related to RT. Besides meta-analysis, establishing international collaboration may help to increase the sample size, reduced confounding factors by standardizing protocols and experimental design, and to perform population-based analysis. Individual gene expression profiles and genetic profiles may be combined to investigate individual variation in radiation induced toxicity more effectively. Genes associated with cell cycle regulation and apoptosis pathways showed significant changes in expression levels 2 hours after irradiation [39]. Gene expression profiles and genetic profiles in future GWAS can be mapped using quantitative levels of expression (eQTLs) mapping [40]. Several cis-acting regulators involved in complex diseases have been identified using eQTLs mapping [40]. By identifying patients with higher susceptibility to radiation, better patient cancer and customization of treatment protocol could be achieved that will improve not only the quality of life, but also the treatment efficacy in future.

 

5.     Conflict of interest

None

 

6.     Funding

This work was supported by grant from the Hong Kong Polytechnic University (RPFG).

 

7.     References

1. Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005; 365: 2041-2054.

2. Ng WT, Lee MC, Hung WM et al. Clinical outcomes and patterns of failure after intensity-modulated radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011; 79: 420-428.

3. Wei WI, Kwong DL. Current management strategy of nasopharyngeal carcinoma. Clinical and experimental otorhinolaryngology 2010; 3: 1-12.

4. Kam MK, Chau RM, Suen J, Choi PH, Teo PM. Intensity-modulated radiotherapy in nasopharyngeal carcinoma: dosimetric advantage over conventional plans and feasibility of dose escalation. Int J Radiat Oncol Biol Phys 2003; 56: 145-157.

5. Peng G, Wang T, Yang KY et al. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. Radiother Oncol 2012; 104: 286-293.

6. Pow EH, Kwong DL, McMillan AS et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006; 66: 981-991.

7. Lee AW, Lau WH, Tung SY et al. Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol 2005; 23: 6966-6975.

8. Lee AW, Tung SY, Chua DT et al. Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2010; 102: 1188-1198.

9. Wells M, MacBride S. Radiation skin reactions. In: Faithfull S and Wells M, eds. Supportive care in radiotherapy, 2003; 135-159.

10. Westbury CB, Yarnold JR. Radiation fibrosis--current clinical and therapeutic perspectives. Clinical oncology 2012; 24: 657-672.

11. Azria D, Betz M, Bourgier C, Jeanneret Sozzi W, Ozsahin M. Identifying patients at risk for late radiation-induced toxicity. Critical reviews in oncology/hematology 2012;84 Suppl 1:e35-41.

12. Barnett GC, West CM, Dunning AM et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer 2009; 9: 134-142.

13. Borgmann K, Roper B, El-Awady R et al. Indicators of late normal tissue response after radiotherapy for head and neck cancer: fibroblasts, lymphocytes, genetics, DNA repair, and chromosome aberrations. Radiother Oncol 2002;64:141-152.

14. Popanda O, Marquardt JU, Chang-Claude J, Schmezer P. Genetic variation in normal tissue toxicity induced by ionizing radiation. Mutat Res 2009;667:58-69.

15. Gatti RA. The inherited basis of human radiosensitivity. Acta Oncol 2001;40:702-711.

16. Faulhaber O, Bristow R. Basis of cell kill following clinical radiotherapy. Application of apoptosis to cancer treatment 2005:293-320.

17. Kiang JG, Garrison BR, Gorbunov NV. Radiation combined injury: DNA damage, apoptosis, and autophagy 2010; 2: 1-10.

18. Bentzen SM. Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat Rev Cancer 2006; 6: 702-713.

19. Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nature reviews. Genetics 2002; 3: 391-397.

20. McCarthy MI, Abecasis GR, Cardon LR et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature reviews. Genetics 2008; 9: 356-369.

21. Alsbeih G, El-Sebaie M, Al-Harbi N et al. SNPs in genes implicated in radiation response are associated with radiotoxicity and evoke roles as predictive and prognostic biomarkers. Radiat Oncol 2013; 8: 125.

22. Li HJ, You YJ, Lin CF et al. XRCC1 codon 399Gln polymorphism is associated with radiotherapy-induced acute dermatitis and mucositis in nasopharyngeal carcinoma patients. Radiat Oncol 2013; 8.

23. Alsbeih G, Al-Harbi N, Al-Hadyan K, El-Sebaie M, Al-Rajhi N. Association between normal tissue complications after radiotherapy and polymorphic variations in TGFB1 and XRCC1 genes. Radiat Res 2010; 173: 505-511.

24. Alsbeih GA, El-Sebaie MM, Al-Rajhi NM et al. Association between XRCC1 G399A polymorphism and late complications to radiotherapy in Saudi head and neck cancer patients. J Egypt Natl Canc Inst 2008; 20: 302-308.

25. Kornguth DG, Garden AS, Zheng Y et al. Gastrostomy in oropharyngeal cancer patients with ERCC4 (XPF) germline variants. Int J Radiat Oncol Biol Phys 2005; 62: 665-671.

26. Lundberg M, Saarilahti K, Makitie AA, Mattila PS. TGFbeta1 genetic polymorphism is associated with survival in head and neck squamous cell carcinoma independent of the severity of chemoradiotherapy induced mucositis. Oral Oncol 2010; 46: 369-372.

27. Pratesi N, Mangoni M, Mancini I et al. Association between single nucleotide polymorphisms in the XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck cancer. Radiother Oncol 2011; 99: 356-361.

28. Werbrouck J, De Ruyck K, Duprez F et al. Acute normal tissue reactions in head-and-neck cancer patients treated with IMRT: influence of dose and association with genetic polymorphisms in DNA DSB repair genes. Int J Radiat Oncol Biol Phys 2009; 73: 1187-1195.

29. Barnett GC, Coles CE, Elliott RM et al. Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study. Lancet Oncol 2012; 13: 65-77.

30. Talbot CJ, Tanteles GA, Barnett GC et al. A replicated association between polymorphisms near TNFalpha and risk for adverse reactions to radiotherapy. Br J Cancer 2012; 107:748-753.

31. Pang Q, Wei Q, Xu T et al. Functional promoter variant rs2868371 of HSPB1 is associated with risk of radiation pneumonitis after chemoradiation for non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2013; 85: 1332-1339.

32. Kerns SL, Ostrer H, Stock R et al. Genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2010; 78: 1292-1300.

33. Kerns SL, Stock R, Stone N et al. A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2013; 85: e21-28.

34. Barnett GC, Elliott RM, Alsner J et al. Individual patient data meta-analysis shows no association between the SNP rs1800469 in TGFB and late radiotherapy toxicity. Radiother Oncol 2012; 105: 289-295.

35. Zhu M-L, Wang M, Shi T-Y et al. No Association between TGFB1 Polymorphisms and Late Radiotherapy Toxicity: A Meta-Analysis. PLoS One 2013; 8: e76964.

36. Kerns SL, Ruysscher DD, Andreassen CN et al. STROGAR - STrengthening the Reporting Of Genetic Association studies in Radiogenomics. Radiother Oncol 2013.

37. West C, Rosenstein BS. Establishment of a radiogenomics consortium. Radiother Oncol 2010; 94: 117-118.

38. Little J, Higgins JP, Ioannidis JP et al. STrengthening the REporting of Genetic Association Studies (STREGA): an extension of the STROBE statement. PLoS Med 2009; 6: e22.

39. Mayer C, Popanda O, Greve B et al. A radiation-induced gene expression signature as a tool to predict acute radiotherapy-induced adverse side effects. Cancer Lett 2011; 302: 20-28.

40. Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M. Mapping complex disease traits with global gene expression. Nature reviews. Genetics 2009; 10: 184-194.

 

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